Daptomycin plus ceftaroline salvage therapy for persistent Staphylococcus epidermidis bacteremia

Key Clinical Message Initial antibiotics for true Staphylococcus epidermidis bacteremia include vancomycin or linezolid, but if bacteremia persists, consideration should be made for salvage combination therapy regimes such as daptomycin with ceftaroline.


| INTRODUCTION
Staphylococcus epidermidis is a coagulase-negative grampositive bacterium that commonly colonizes the skin and mucous membranes of humans. 1 It is frequently isolated from blood culture collection and is usually considered a contaminant species; however, its relevance in healthcareassociated infections is becoming more recognized. 2It is the most common cause of nosocomial blood infections, usually associated with vascular access lines, because of its ability to form bacterial biofilms. 1Management of S. epidermidis bacteremia involves the removal of infected prosthetic material and an adequate course of effective antimicrobials. 3Bacteremia can occasionally be persistent, with a recent review reporting a median duration of 3 days. 4We present a challenging case of persistent S. epidermidis bacteremia over 21 days, where a novel antibiotic regimen was utilized for definitive treatment.

| CASE REPORT
A gentleman in his 70s from home was admitted to a tertiary Australian hospital with several days of atraumatic bilateral knee arthritis.His background history included type 2 diabetes mellitus, stage 3b chronic kidney disease, atrial fibrillation, hypertension, and gout.Based on examination findings and his history of poor adherence to allopurinol, he was commenced on a short course of prednisone 25 mg daily for a clinically suspected polyarticular gout flare and improved significantly.His admission was prolonged due to requiring aged care home placement.
One month into admission, he became febrile with no focal signs or symptoms.Peripheral blood cultures collected during the initial septic work-up flagged positive after 24 h in both aerobic and anerobic bottles with S. epidermidis.He had no audible murmurs, nor did he have any intravenous cannulas or prosthesis, and so this result was initially deemed to be clinically insignificant.He continued to have fevers while remaining hemodynamically stable over the next 3 days, and subsequent blood cultures continued to isolate S. epidermidis after 24 h incubation, raising concerns for true bacteremia.The isolate was methicillin resistant but susceptible to vancomycin with a minimum inhibitory concentration (MIC) of 2 mg/L, confirming sensitivity according to the European Committee of Antimicrobial Susceptibility Testing (EUCAST) breakpoint of 4 mg/L for coagulase-negative Staphylococci. 5 Intravenous vancomycin was commenced, with dosing guided by Bayesian modeling software as per consensus guidelines. 6His body mass index was 35 kg/m 2 , and creatinine clearance was 24 mL/min based on his ideal body weight.He was started on vancomycin 1000 mg, which was later increased to 1200 mg daily.AUC/MIC >400 mg.h/L was achieved by the fifth dose, and intermittent vancomycin was continued for 6 days.All intravenous catheters were reviewed and changed routinely as per local hospital policy.Unfortunately, he was unable to clear his bacteremia, and so he was switched to a continuous vancomycin infusion of 1300 mg daily to reduce variation in concentrations.Vancomycin remained therapeutic with an AUC/MIC of 500 mg.h/L on continuous infusion, which was given for another 7 days.Despite over 10 days of vancomycin at therapeutic levels, his daily blood cultures continued to isolate S. epidermidis.
Investigations were performed to look for sources of persisting bacteremia despite therapeutic levels of vancomycin.A computed tomography scan was performed, showing no focal abnormalities in his chest, abdomen, or pelvis.He underwent a transesophageal echocardiography, which revealed a heavily calcified degenerative stenotic aortic valve with Lambl's excrescences but no mobile vegetation.A positron emission tomography scan was performed to look for indolent sources of bacteremia, but it revealed no definitive findings.After almost 2 weeks into therapy, he developed superficial thrombophlebitis in an intravenous cannula site, which was thought to be contributory but not the root cause for the persistent bacteremia.
F I G U R E 1 Antibiotic regime with corresponding peak temperature chart and blood culture results.
Linezolid MIC was 2 mg/L, considered sensitive according to EUCAST, 5 and so therapy was changed to oral linezolid 600 mg twice daily after 12 days of vancomycin.Despite achieving a supratherapeutic linezolid trough level of 11.1 mg/L 48 h after initiation, with improvement in fevers and inflammatory markers, his blood cultures remained positive for S. epidermidis between 24 and 48 h of incubation.
After 21 days of persistent S. epidermidis bacteremia (Figure 1), despite appropriately targeted antimicrobials with maintained MIC to both vancomycin and linezolid, his therapy was changed to intravenous daptomycin 8 mg/kg every 48 h with synergistic ceftaroline 300 mg three times daily, dose-adjusted based on his estimated creatinine clearance of 24 mL/min.This decision was made based on available literature for persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremias. 7Daptomycin and ceftaroline MICs for the isolate were 0.25 and 0.125 mg/L, respectively; the former were considered sensitive as per EUCAST, 5 and the latter had no established breakpoint.Blood cultures taken 1 day after starting combination salvage therapy isolated no growth.He subsequently had a further five blood cultures that remained negative after 5 days of incubation.It was noted that all previous positive blood cultures had isolated the organism within 48 h, and so he was deemed to have cleared the bacteremia.Given his prolonged illness, he was treated as a complicated endovascular infection with 4 weeks of daptomycin and ceftaroline following blood culture clearance, administered via the outpatient parenteral antimicrobial therapy service, before stepping down to oral linezolid for a further 2 weeks.He remained clinically well, and surveillance blood cultures taken 4 weeks after completing antibiotic therapy remained negative.

| DISCUSSION
The combination of daptomycin and ceftaroline for complicated MRSA bacteremias has been well described in retrospective studies as a salvage therapy option in persistent cases. 7Antimicrobial options for persistent S. epidermidis bacteremia are significantly lacking, particularly in the absence of a focal source.There are previous reports documenting the use of daptomycin alone with some success, including hemodialysis-associated infective endocarditis 8 and line-associated neonatal sepsis. 9A further two cases of prosthetic valve infective endocarditis were treated with a combination of daptomycin and ceftaroline. 10Previous data in persistent MRSA bacteremias have suggested that heavy vancomycin exposure increases the risk of daptomycin failure, 11 and thus lead us to decide on combination therapy.The importance of a multidisciplinary team approach in managing complex infections was also highlighted in this case, with significant contributions made by both the medical and antimicrobial stewardship pharmacy teams in decision-making and antibiotic dose adjustment.We believe this case serves as an example of successful clearance of persistent bacteremia using this novel treatment approach as salvage therapy in the absence of any persistent focal source for S. epidermidis.